DiagnosisClinical DiagnosisThe diagnosis of Muenke syndrome is suggested by clinical findings and established by the presence of the FGFR3 mutation c.749C>G (p.Pro250Arg). Phenotypic variability in individuals with Muenke syndrome is considerable. Skull phenotype, as determined by radiographs and/or CT scan of the skull can include the following: Unilateral coronal craniosynostosis with anterior plagiocephaly (asymmetry of the skull and face) with the following physical findings:Facial asymmetryIpsilateralFlattening of the forehead Elevation of the superior orbital rim Elevation of the eyebrow Anterior placement of the ear anteriorDeviation of the nasal root Bossing of the foreheadContralateralBulging of the frontal boneDepression of the eyebrowBilateral coronal craniosynostosis that typically results in brachycephaly (broad skull), although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Physical findings:Temporal bossing (which is a helpful diagnostic sign) Facial symmetryReduced anterior-posterior dimension of skull Synostosis of other sutures (lambdoid, metopic, sagittal)Macrocephaly without craniosynostosisNormal skull (no synostosis, no macrocephaly)Variable features similar to other FGFR-related craniosynostosis syndromes (e.g., Pfeiffer syndrome and/or Crouzon syndrome) and Saethre-Chotzen syndrome include: Developmental delayIntellectual disabilityLearning disorderHigh-arched palateMidface hypoplasiaOcular hypertelorismPtosisProptosis (rare, but has been reported)StrabismusHearing loss (typically mild and sensorineural)Brachydactyly (short fingers and toes)Cutaneous syndactyly (rarer finding; reported in 13 individuals with Muenke syndrome)Broad toesBroad thumbsClinodactylyNote: Absence of minor clinical signs of Muenke syndrome may lead to misdiagnosis of an affected individual. For example, an individual with craniosynostosis who does not have extracranial findings may be misdiagnosed with "isolated" craniosynostosis.The extracranial radiographic features of Muenke syndrome are variable and may include the following: Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [Muenke et al 1997, Trusen et al 2003]Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [Muenke et al 1997, Trusen et al 2003]Thimble-like (short and broad) middle phalanges of the hands and feetEpiphyseal coningNote: (1) Didolkar et al [2009] reported an individual presenting with polyarthralgia and hearing loss who was determined to have Muenke syndrome when hand and foot radiographs revealed bilateral non-osseous calcaneo-navicular fusions, osseous cuboid-lateral cuneiform fusions, bilateral capitate and hamate osseous fusions, cone-shaped epiphysis of the middle phalanges, and brachydactyly. Barbosa et al [2009] reported an individual with intellectual disability whose hand and foot radiographs showed an osteochondroma (a previously unreported finding in Muenke syndrome) and bilateral fusion of the calcaneus and cuboid. These cases demonstrate how extracranial findings may serve as a clinical clue to the presence of the p.Pro250Arg mutation, particularly in individuals who do not have craniosynostosis. (2) Some fusions are not seen on radiographs until skeletal maturity is reached. Trusen et al [2003] studied the radiographs of persons with Muenke syndrome and Saethre-Chotzen syndrome. He found that five of eight individuals with Muenke syndrome had partial syndactyly and that two of eight had calcaneo-cuboid fusion. In this series, calcaneo-cuboid fusion was only detected in individuals with Muenke syndrome. Molecular Genetic TestingGene. FGFR3 is the only gene known to be associated with Muenke syndrome.Clinical testingTargeted mutation analysis. By definition all individuals with Muenke syndrome have an FGFR3 c.749C>G point mutation, resulting in a p.Pro250Arg substitution [Bellus et al 1996].Table 1. Summary of Molecular Genetic Testing Used in Muenke SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityFGFR3Targeted mutation analysisp.Pro250Arg 2 >99%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Muenke syndrome is defined by the FGFR3 c.749C>G (p.Pro250Arg) mutation.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. Findings on the initial evaluation (complete medical history, physical examination, review of systems, and family history) should help direct selection of the most appropriate molecular study. Note: At this stage, radiographs may be useful in providing clues to the presence of Muenke syndrome, particularly in individuals with a family history and/or subtle physical signs of Muenke syndrome including mild hearing loss, intellectual disability, and/or macrocephaly. Syndromic bilateral coronal synostosis. It is customary to perform a "craniosynostosis panel" that typically consists of molecular genetic testing of FGFR1, FGFR2, FGFR3 – including the defining FGFR3 c. 749C>G (p.Pro250Arg) mutation, and TWIST (see Differential Diagnosis).An algorithm for molecular genetic testing based on clinical findings proposes to improve the efficiency and cost effectiveness of molecular testing [Chun et al 2003]. An additional three-tiered algorithm has been suggested [Wilkie et al 2006]:Tier 1. Detects most intragenic mutations causing Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, Muenke syndrome, and Saethre-Chotzen syndrome (FGFR1 exon 7 [IIa]; FGFR2 exons 8 [IIIa] and 10 [IIIc]; FGFR3 exons 7 [IIIa] and 10 [TM]; and TWIST1 [exon 1]). Tier 2. Detects rarer mutations associated with Crouzon syndrome and Pfeiffer syndrome (FGFR2 exons 3,5,11, and 14-17).Tier 3. Detects heterozygous gene deletions in TWIST1 (Saethre-Chotzen syndrome) and EFNB1 (craniofrontonasal syndrome). Apparently isolated coronal synostosis. Some experts recommend that all probands with apparently isolated coronal synostosis be tested for the defining FGFR3 c. 749C>G (p.Pro250Arg) mutation because it is difficult to differentiate Muenke syndrome from true coronal nonsyndromic craniosynostosis based on clinical evaluation alone [Renier et al 2000, Tsai et al 2000, Thomas et al 2005, Boyadjiev 2007, Kimonis et al 2007, Seto et al 2007]. In the first cohort-based analysis of the genetic basis of craniosynostosis, Wilkie et al [2010] found that 24% of identified genetic causes of syndromic and nonsyndromic synostosis resulted from the defining Muenke syndrome FGFR3 mutation.It is important to establish the molecular diagnosis of Muenke syndrome: For management because of the significantly increased rate of cranial reoperation, hearing impairment, and developmental delay in Muenke syndromeFor selective screening of related abnormalities For genetic counselingPrenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersThe following are clinically distinct disorders and their causative FGFR3 mutations. Note: Amino acid changes are given as in the original publications.Thanatophoric dysplasia type 1. p.Arg248Cys, p.Ser249Cys, p.Gly370Cys, p.Ser371Cys, p.Tyr373Cys, p.Lys650Glu and several types of codon 807 substitutions [Rousseau et al 1994, Bellus et al 1995, Tavormina et al 1995] Achondroplasia. Point mutations at codon 380, p.Gly380Arg [Rousseau et al 1994, Shiang et al 1994]Hypochondroplasia. Mutations dispersed in FGFR3; p.Asn540Lys accounts for 60%-65% of affected persons [Bellus et al 1995, Prinos et al 1995, Prinster et al 1998].Lacrimo-auriculo-dento-digital syndrome (OMIM 149730). p.Asp513Asn [Rohmann et al 2006]Camptodactyly, tall stature, and hearing loss (CATSHL) syndrome (OMIM 610474). p.Arg621His [Toydemir et al 2006]Crouzon syndrome with acanthosis nigricans/Crouzonodermoskeletal syndrome (see FGFR-Related Craniosynostosis Syndromes). p.Ala391Glu [Meyers et al 1995, Wilkes et al 1996]Note: An individual with isolated unilateral coronal synostosis and her mildly affected mother were found to be heterozygous for a point mutation in FGFR3 resulting in p.Pro250Leu [Schindler et al 2002]. Although Schindler et al [2002] considered this family to have Muenke syndrome, it is not clear if these individuals (who have a different mutation at the same position as the defining p.Pro250Arg mutation) actually have Muenke syndrome because no additional individuals with a phenotype resembling Muenke syndrome have been reported to have missense mutations at codon 250 encoding a substitution other than proline to arginine.}

Natural HistoryCraniosynostosis. Coronal synostosis may be bilateral or unilateral. Bilateral coronal synostosis results in brachycephaly (broad skull); other head shapes may include turribrachycephaly (a "tower-shaped" skull) or cloverleaf-shaped skull in severe cases. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face). Occasionally, other sutures may be involved. One individual with Muenke syndrome had trigonocephaly resulting from metopic suture synostosis; his affected mother had bicoronal synostosis [van der Meulen et al 2006]. Rarely, pansynostosis occurs. In one report, one of ten family members with the p.Pro250Arg mutation had pansynostosis [Golla et al 1997]. This individual, the most severely affected family member, also had ocular proptosis. Craniosynostosis in Muenke syndrome most commonly involves the coronal suture. Bilateral coronal synostosis appears to be more common than unilateral synostosis. Renier et al [2000] determined that 71% of individuals with Muenke syndrome had bilateral coronal synostosis and 29% had unilateral coronal synostosis. Keller et al [2007] reported 66% with bilateral coronal synostosis and 34% with unilateral coronal synostosis. Craniosynostosis is not always present in individuals with Muenke syndrome: In 72 individuals from 24 families, nine (12.5%) persons known to be heterozygous for the FGFR3 p.Pro250Arg mutation had no evidence of craniosynostosis [Renier et al 2000]. In a family of seven, five had coronal synostosis and two were phenotypically normal [Moko & Blandin de Chalain 2001]. In these cases, extracranial findings (i.e., radiographic findings of carpal and tarsal fusions, short and broad middle phalanges, cone-shaped epiphysis, or hearing loss), when present, helped support the diagnosis of Muenke syndrome.Craniofacial features that may result from craniosynostosis are summarized in Diagnosis. Rarer craniofacial features include malar hypoplasia, a short upturned nose, a “hook-shaped” nasal tip, deviation of the nasal septum, a short nose with a flat nasal bridge, dental malocclusion, mild retrognathia, hypoplastic auricles, and low-set ears.Extracranial findingsHearing loss. Although initial studies revealed that at least one third of individuals with Muenke syndrome have mild to moderate sensorineural hearing loss [Muenke et al 1997, Kress et al 2006, de Jong et al 2010], more recent studies indicate that all individuals with Muenke syndrome are likely to have some degree of hearing loss, usually mild [Doherty et al 2007, Honnebier et al 2008, Mansour et al 2009]. The exact cause of the hearing loss is unknown. Mansour et al [2009] determined that in the mouse model of Muenke syndrome all mice had low-frequency sensorineural hearing loss with relative high-frequency sparing and histologic changes in the organ of Corti and cochlear duct. Additionally, some individuals with Muenke syndrome have had recurrent episodes of otitis media treated with multiple myringotomy tube placements [Didolkar et al 2009]. In a large family several individuals who were heterozygous for the FGFR3 p.Pro250Arg mutation had moderate, bilateral sensorineural hearing loss but no craniosynostosis [Hollway et al 1998]; the sensorineural hearing loss was similar to the autosomal dominant form of deafness (DFNA6), which has been mapped to 4p16.3, the same region as FGFR3 [Lowry et al 2001]. In a subsequent study by Bespalova et al [1999], no evidence for the p.Pro250Arg mutation was found in the individuals with DFNA6. Developmental delay. Developmental delay and/or intellectual disability, usually mild, have been reported in approximately one third of individuals [Muenke et al 1997, Kress et al 2006]. In a study of intellectual outcomes following protocol management in four persons with Muenke syndrome followed from birth to skeletal maturity compared to persons with Crouzon syndrome and Pfeiffer syndrome, Flapper et al [2009] found that individuals with Muenke syndrome and Pfeiffer syndrome were more likely to be intellectually impaired than were individuals with Crouzon syndrome. One of the four with Muenke syndrome had moderate intellectual disability (IQ <70) and a history of behavioral problems; two had borderline intellectual disability (IQ 70-80) and required special education; and one was of average intelligence (IQ 90-110), completed high school without difficulty, and is currently training to be a pilot. Honnebier et al [2008] did not find gross mental delays in 15/16 individuals; however, no formal neurocognitive evaluation was performed. One individual had autism. Reardon et al [1997] found that four of nine persons evaluated had intellectual impairment: two had mild to moderate mental handicap requiring special education; one had developmental delay requiring special education; one was described as having severe developmental delay.In twins with Muenke syndrome and bicoronal suture synostosis reported by Escobar et al [2009], one twin had generalized anxiety disorder (GAD) and attention-deficit-hyperactivity disorder (ADHD) at age seven years; the other twin had pervasive developmental disorder (PDD), developmental delay (DD), ADHD, and structural brain anomalies on MRI including a large porencephalic cyst of the occipital horn of the left ventricle, hydrocephalus, and absence of the corpus callosum. Of note, both twins developed bilateral sensorineural hearing loss requiring hearing aids.One study found a slightly lower IQ in individuals with craniosynostosis with Muenke syndrome compared to individuals with craniosynostosis who do not have the defining mutation [Arnaud et al 2002]. The etiology of the developmental delay, intellectual disability, and behavioral problems reported in individuals with Muenke syndrome is yet to be elucidated. Additionally, it is not yet known whether hearing loss plays a role in the developmental delay or whether individuals without craniosynostosis have a better intellectual/functional outcome as adults.Strabismus. The most common ocular finding in Muenke syndrome is strabismus. In one family with six members with Muenke syndrome, all six had strabismus [Yu et al 2010]. A study of the ocular phenotype of Muenke syndrome showed that compared to the average pediatric population, children with Muenke syndrome have a higher incidence of strabismus (66%), anisometropia, epicanthal fold changes, ocular hypertelorism, downward lateral canthal dystopia, and amblyopia [Jadico et al 2006]. In a larger series, the incidence of strabismus was 14/36 (39%) [de Jong et al 2010]. One individual had paralytic strabismus secondary to a cranial nerve VI deficit [Lowry et al 2001].Limb findings. Most individuals with Muenke syndrome have normal-appearing hands and feet with normal range of motion of all joints; therefore, many of the limb findings in Muenke syndrome are identified during the diagnostic work-up when radiographs reveal findings such as short, broad middle phalanges of the fingers, absent or hypoplastic middle phalanges of the toes, carpal and/or tarsal fusion, and cone-shaped epiphyses [Hughes et al 2001]. Table 2. Rare Findings in Persons with Muenke SyndromeView in own windowFinding# of Persons with FindingReferencesOsteochondroma1Barbosa et al [2009]Laterality disorder
Hepatoblastoma ¹ 1Baynam & Goldblatt [2010]Generalized anxiety disorder
ADHD1Escobar et al [2009]Autism1Honnebier et al [2008]Pervasive developmental disorder
Esophageal atresia with tracheo-esophageal fistula
Atrial septal defect
Ventricular septal defect ² 1Escobar et al [2009]Choanal atresia1Hughes et al [2001]Scoliosis1Hughes et al [2001]Sprengel shoulder
Klippel-Feil anomaly
Fused ribs
Short neck
Low posterior hairline
Paralytic strabismus1Lowry et al [2001]Distal tapering of the fingers1Lowry et al [2001]Cutaneous syndactyly13Golla et al [1997]
Passos-Bueno et al [1999]
Chun et al [2002]
Trusen et al [2003]
Shah et al [2006]
Baynam & Goldblatt [2010]Breast cancer2Hughes et al [2001]
Sahlin et al [2007]Pituitary adenoma1Sahlin et al [2009]Sudden infant death1Shah et al [2006]Absent right auditory meatus1Shah et al [2006]Structural brain anomalies ^{33 3Grosso et al [2003]
Escobar et al [2009]
Yu et al [2010]1. This pregnancy was complicated by maternal IDDM; father had the defining Muenke syndrome mutation.2. This pregnancy was complicated by maternal use of nortriptyline.3. Structural anomalies found include: hippocampus and bilateral medial temporal dysgenesis in one person [Grosso et al 2003], bilateral lateral ventricular dilatation and a small cerebellum in one person [Yu et al 2010], and porencephalic cyst of the occipital horn of left ventricle and absence of the corpus callosum in one person [Escobar et al 2009]. Of note, the individual reported in Grosso et al [2003] was described as developmentally normal. Minor clinical signs/asymptomatic heterozygotesSome individuals heterozygous for the FGFR3 p.Pro250Arg mutation have no clinical or radiographic features of Muenke syndrome [Robin et al 1998, Moko & Blandin de Chalain 2001]. Some individuals with Muenke syndrome have minor clinical signs such as macrocephaly [Gripp et al 1998] and subtle facial findings without craniosynostosis [Gripp et al 1998, Robin et al 1998, Moko & Blandin de Chalain 2001, Sabatino et al 2004, Didolkar et al 2009]; some appear clinically unaffected until their radiographs are examined [Muenke et al 1997]. These individuals may not come to medical attention until the birth of a more severely affected child.}

Genotype-Phenotype CorrelationsNo genotype-phenotype correlations are observed because all individuals with Muenke syndrome have the same mutation in FGFR3.

Differential DiagnosisUnclassified brachycephaly refers to bilateral coronal synostosis in individuals who do not have any of the classic craniosynostosis syndromes (e.g., Pfeiffer syndrome, Crouzon syndrome). Following discovery of the FGFR3 p.Pro250Arg mutation, one survey of a group with unclassified brachycephaly found that 52% had Muenke syndrome [Mulliken et al 1999].Syndromic craniosynostosis. Table 3 compares and contrasts Muenke syndrome with similar craniosynostosis syndromes. Because of phenotypic overlap and/or mild phenotypes, clinical differentiation of these syndromes may be difficult.Phenotypic variation in Muenke syndrome includes the following:A distinct "Muenke" syndrome phenotype includes: uni- or bilateral coronal synostosis, midface hypoplasia, broad toes, and brachydactyly.Some individuals clinically diagnosed with Crouzon syndrome, Pfeiffer syndrome, or Saethre-Chotzen syndrome are ultimately found to have Muenke syndrome when molecular genetic testing is performed. Chun et al [2002] examined individuals clinically identified as having the Saethre-Chotzen syndrome phenotype. Of 11 individuals identified as having the Saethre-Chotzen phenotype, four (44%) were found to have the p.Pro250Arg mutation. Sahlin et al [2009] describes a family with the Saethre-Chotzen syndrome (SCS) phenotype. The proband’s father was diagnosed with Saethre-Chotzen syndrome, in addition to the proband and her son. Sequence analysis showed the p.Pro250Arg mutation in exon 7 of FGFR3. In another case, a mother and a daughter were diagnosed with Muenke syndrome following the sudden unexpected death of the daughter [Shah et al 2006]. The mother had been diagnosed in infancy with Treacher Collins syndrome. A proband with craniosynostosis and her father both had epidermal hyperplasia (Beare-Stevenson-like anomalies) [Roscioli et al 2001]. (See FGFR-Related Craniosynostosis Syndromes.)Additional, less common extracranial findings reported in Muenke syndrome are listed in Table 2. It is not clear whether some of these findings are a consequence of the p.Pro250Arg mutation or whether they are coincidental.Table 3. A Comparison of Muenke Syndrome with Other FGFR-Related Craniosynostosis Syndromes and Saethre-Chotzen SyndromeView in own windowCraniosynostosis Phenotype"Classic" Features Common to Muenke SyndromeFeatures Unlike Muenke SyndromeCrouzon syndrome– Bilateral coronal synostosis
– Normal extremities
– Normal intellect
– Strabismus
– Ocular hypertelorism
– Hearing deficit (conductive vs. sensorineural in Muenke syndrome)– Significant proptosis
– Mandibular prognathism
– Beaked nose
– Lack of digital abnormalities
– Maxillary hypoplasia
– Progressive hydrocephalus
– Cervical spine fusionsSaethre-Chotzen syndrome– Uni- or bilateral coronal synostosis
– Brachycephaly
– Facial asymmetry
– Midface hypoplasia
– Normal intellect OR mild-to-moderate developmental delay
– Ptosis
– Ocular hypertelorism
– Strabismus
– Downslanting palpebral fissures
– High arched palate
– Brachydactyly– Small ear pinna with prominent crus
– Syndactyly of fingers 2-3
– Low frontal hairline
– Duplication of the distal phalanx of the hallux
– Fusion of cervical vertebrae
– Increased ICPPfeiffer syndrome type 1– Bilateral coronal synostosis
– Midface hypoplasia
– Ocular hypertelorism
– Downslanting palpebral fissures
– Strabismus
– Highly arched palate
– Brachydactyly
– Normal intellect
– Broad thumbs and great toes
– Variable brachydactyly– Medial deviation of thumbs and great toes
– Lateral deviation of thumbs and great toes away from other digits
– Malformed and fused phalanges
– Symphalangism
– Partial soft tissue syndactyly of fingers and toes
– Mandibular prognathism
– Ocular proptosisJackson-Weiss syndrome ^{1– Bilateral coronal synostosis
– Midface hypoplasia
– Tarsal fusions
– Broad great toes– Metatarsal fusions
– Abnormal tarsal bones
– Medial deviation of great toes
– Cutaneous syndactylyApert syndrome– Bilateral coronal synostosis
– Broad great toes
– Ocular hypertelorism
– Downslanting palpebral fissures
– Strabismus
– Highly arched palate
– Hearing loss– Disproportionately severe midface hypoplasia
– Ocular proptosis
– Severe, symmetric soft tissue/bony syndactyly of fingers and toes
– Broad thumbs
– Lateral deviation of thumbs and great toes
– Fusion of cervical vertebrae
– Acneiform eruptionsBeare-Stevenson cutis gyrata– Bilateral coronal synostosis
– Normal extremities– Furrowed palms and soles
– Widespread cutis gyrata and acanthosis nigricans
– Prominent umbilicus
– Moderate intellectual disability
– Seizures1. Jackson-Weiss syndrome is most likely limited to members of the original pedigree.An identical proline-to-arginine mutation occurs at analogous positions in FGFR1, FGFR2, and FGFR3 (Figure 1):FigureFigure 1. Diagram of the C>G missense mutations that result in a proline-to-arginine substitution at analogous positions in the protein products of FGFR1, FGFR2, and FGFR3 p.Pro252Arg in FGFR1 causes Pfeiffer syndrome (FGFR1 reference sequences NM_023110.2, NP_075598.2).p.Pro253Arg in FGFR2 causes Apert syndrome (FGFR2 reference sequences NM_022970.2, NP_075259.2).p.Pro250Arg in FGFR3 causes Muenke syndrome (see Table 5).For an excellent overview of other primary and secondary forms of craniosynostosis, see FGFR-Related Craniosynostosis Syndromes.Nonspecific craniosynostosis. Table 4 summarizes the detection rate for the p.Pro250Arg mutation among large craniosynostosis populations with nonspecific phenotypes.Table 4. Craniosynostosis Clinic Populations with a Nonspecific Phenotype Tested for the p.Pro250Arg FGFR3 Mutation View in own windowPhenotypep.Pro250Arg Mutation
Detection FrequencyReferences"Apparently isolated" unilateral coronal synostosis4%-12%Moloney et al [1997]
Reardon et al [1997]
Gripp et al [1998]
Renier et al [2000]
Mulliken et al [2004] "Apparently isolated" or "nonsyndromic" bilateral coronal synostosis~30%-40%Moloney et al [1997]
Renier et al [2000] Proband with coronal synostosis and
positive family history (FGFR1 & FGFR2mutations excluded)9%-70%Reardon et al [1997],
Renier et al [2000] Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).}

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Muenke syndrome, the following evaluations are recommended:Assessment of suture involvement by skull radiographs or preferably 3D skull CTAssessment for hydrocephalus with brain CT or MRIAssessment for exposure keratopathyHearing assessmentDevelopmental assessment in childrenOphthalmologic assessment including screening for strabismus and vision. Additionally, this assessment should include fundoscopy to assess for papilledema, a finding that is present when intracranial pressure (ICP) is increased. Radiographic assessment of hands and feetTreatment of ManifestationsChildren with Muenke syndrome and craniosynostosis should be referred to a craniofacial clinic with pediatric experience. These individuals benefit most from a multidisciplinary approach to care. A craniofacial clinic associated with a major pediatric medical center usually includes: a surgical team (craniofacial surgeon and neurosurgeon), medical geneticist, ophthalmologist, otolaryngologist, pediatrician, radiologist, psychologist, dentist, audiologist, speech therapist, and social worker. Other disciplines are involved as needed.Depending on the severity, the first craniosynostosis repair is typically performed between age three and six months. This procedure is usually transcranial (i.e., the skull is opened down to the dura so that the bones can be physically repositioned during a procedure such as a midface advancement). For a more thorough discussion, see FGFR-Related Craniosynostosis Syndromes.Following transcranial repair, the need for a second procedure is increased in those with Muenke syndrome compared to those with craniosynostosis without the defining mutation. The reasons for a second procedure vary by individual and can include: Severe initial clinical presentation requiring a staged transcranial repairRecurrent deformity requiring a second transcranial repair The need for a surgical revision for aesthetic reasons (typically temporal bulging) is increased in multiple series [Renier et al 2000, Cassileth et al 2001, Arnaud et al 2002, Thomas et al 2005, Honnebier et al 2008]. According to Thomas et al [2005], individuals with craniosynostosis and the defining mutation were more likely to require early intervention with a posterior release operation (at age ~6 months) to prevent excess frontal bulging than were those without the defining mutation. Cranial vault abnormalities including temporal bulging and recurrent supraorbital retrusion requiring extracranial contouring (i.e., use of a cement such as calcium phosphate to contour the surface of the skull)Postoperative increased ICPIn the study of Thomas et al [2005], seven of 29 individuals (24.1%) with the p.Pro250Arg mutation underwent a second surgery (6/7 had increased ICP) as compared to two of 47 (4.3%) without the mutation. This difference in reoperation rate was statistically significant (p=0.048). In the report of Honnebier et al [2008] 16 individuals with Muenke syndrome required a second procedure: seven required a second transcranial procedure; 15 were expected to undergo extracranial contouring. Note that none had increased ICP. In Muenke syndrome a discrepancy between severity of the craniofacial findings (e.g., severe midface hypoplasia, hypertelorism) and neurologic findings (e.g., increased ICP, hydrocephalus, structural brain anomalies, severe developmental delay or severe intellectual disability) has been noted [Lajeunie et al 1999, Arnaud et al 2002, Honnebier et al 2008]: severe early clinical findings such as recurrent deformity and the need for a second major procedure did not correlate with postoperative risk for increased ICP. Prevention of Secondary ComplicationsEarly surgical reconstruction of craniosynostosis may reduce the risk for secondary complications such as those related to increased ICP. SurveillanceThe following are appropriate:Regular developmental assessments of affected childrenPeriodic repeat audiograms because some children with Muenke syndrome and craniosynostosis develop hearing loss despite passing their newborn hearing screens [Doherty & Muenke, personal observation]Part of protocol-driven care and management includes annual multidisciplinary reviews and periodic review by a social work team. Protocol-driven approaches to surveillance currently in use include those of Flapper et al [2009] and de Jong et al [2010].Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Muenke Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFGFR34p16​.3Fibroblast growth factor receptor 3FGFR3 @ LOVDFGFR3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Muenke Syndrome (View All in OMIM) View in own window 134934FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3 602849MUENKE SYNDROME; MNKESMolecular Genetic PathogenesisThe c.749C>G transversion in FGFR3 is estimated to occur at a rate of 7.6-8x10^-6 per haploid genome, one of the highest known mutation rates for a transversion [Moloney et al 1997, Rannan-Eliya et al 2004].Normal allelic variants. Human FGFR3 is 16.7 kb long and is composed of 17 coding exons [Perez-Castro et al 1997]. Pathologic allelic variants. Figure 2 demonstrates the p.Pro250Arg protein change in FGFR3. FigureFigure 2. Schema of the FGFR3 protein
The loops represent the three immunoglobulin domains (left to right: IgI, IgII, IgIII). The p.Pro250Arg protein change (indicated with a black dot) is in the linker region between the second and third (more...)Table 5. Selected FGFR3 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.749C>Gp.Pro250ArgNM_000142​.4
NP_000133​.1c.749C>T ^{1p.Pro250Leu 1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. It is unclear if this mutation results in Muenke syndrome (see Genetically Related Disorders).Normal gene product. The FGFR family is a group of receptor tyrosine kinases. FGFRs 1-4 have an extracellular ligand-binding domain containing three immunoglobulin-like loops, a single-pass transmembrane domain, and a split intracellular kinase domain. FGFRs bind fibroblast growth factors (FGFs) and dimerize in order to effect downstream intracellular signaling [Green et al 1996]. FGFR3 negatively regulates chondrocyte differentiation and proliferation in developing endochondral bone (appendicular skeleton) [Ornitz & Marie 2002]. The genetics of intramembranous bone (skull vault) formation are complex, and the role of FGFR3 is not yet well understood. FGFR3 is detected in coronal suture osteogenic fronts but at lower levels than FGFR1 and FGFR2 [Iseki et al 1999]. FGFR3 is mainly expressed in mature chondrocytes of the cartilage growth plate [Cunningham et al 2007]. FGFR3 mRNA is found in its highest amounts in the developing CNS [Robin 1999]. It is also present in the skeletal precursors for all bones during the period of endochondral ossification and resting cartilage [Robin 1999]. Abnormal gene product. The p.Pro250Arg mutation results in enhanced FGF binding [Ibrahimi et al 2004]. This mutation is located in the linker region between the second and third immunoglobulin-like domains (Figure 2) [Park et al 1995, Wilkie et al 1995]. Kinetic ligand binding studies and x-ray crystallography of linker region mutations demonstrate that the mutation results in increased ligand affinity (FGF9) and altered specificity [Cunningham et al 2007]. Overactivation of FGFR3 appears to lead to craniosynostosis because bone differentiation is accelerated [Funato et al 2001].Fgfr3 knockout mice have elongated tails and hind limbs, implying that FGFR3 has a role in slowing skeletal growth [Robin 1999] and indicating that FGFR3 mutations are hypermorphic, causing the mutated gene product to over-perform its normal function.}